X-Adrenoleukodystrophy (X-ALD) is an inherited neurological disorder. Mutation/deletion of the ALD gene product (ALDP) results in deficient activity of lignoceroyl-CoA ligase, and 13-oxidation of VLC fatty acids which leads to the pathognomonic accumulation of VLC fatty acids with secondary inflammatory disease and loss o oligodendrocytes and dysmyelination/demyelination. The objective of this proposal is to determine the functional organization of ALDP/lignoceroyl-CoA ligase in peroxisomes, and to elucidate the molecular events responsible in VLC fatty acid-induced inflammatory disease leading to dysfunction/loss of oligodendrocytes. Studies are designed to determine the amino acid domains of ALDP that interact with lignoceroyl-CoA ligase for it's functional organization in the beta-oxidation of very long chain (VLC) fatty acids in peroxisomes and to elucidate the possible role of VLC fatty acid-induced derangements in the induction/propagation of neuroinflammatory disease and loss of oligodendrocytes in X-ALD. Studies are also designed to delineate the regulation of VLC fatty acid 13-oxidation and induction of expression of the ALD related gene product (ALDRP), an ALD related protein, for correction of the metabolic defect in X-ALD cultured skin fibroblasts and in tissues of ALD knockout mice. The proposed studies use state of the art techniques and will provide a better understanding of the regulation of VLC fatty acid metabolism in control and X-ALD and functional organization of ALDP/lignoceroyl-CoA ligase, and correction of the metabolic as well as the neuroinflammatory disease in X-ALD. We are very excited about the possibility that basic studies from our laboratory may become the basis for therapeutic approaches for X-ALD.